Efficacy and safety of eribulin in patients with locally advanced or metastatic breast cancer not meeting trial eligibility criteria: A retrospective study

The efficacy and safety of eribulin in patients with locally advanced or metastatic breast cancer has been demonstrated in phase III trials. However, as patients receiving eribulin in daily practice do not necessarily meet all the eligibility criteria of clinical trials, data for such patients are limited.

Iizumi et al BMC Cancer (2017) 17:819 DOI 10.1186/s12885-017-3846-8 RESEARCH ARTICLE Open Access Efficacy and safety of eribulin in patients with locally advanced or metastatic breast cancer not meeting trial eligibility criteria: a retrospective study Sakura Iizumi1,2, Tatsunori Shimoi1,3* , Natsuko Tsushita1, Seiko Bun4, Akihiko Shimomura1, Emi Noguchi1, Makoto Kodaira5, Mayu Yunokawa1, Kan Yonemori1, Chikako Shimizu1, Yasuhiro Fujiwara1 and Kenji Tamura1 Abstract Background: The efficacy and safety of eribulin in patients with locally advanced or metastatic breast cancer has been demonstrated in phase III trials However, as patients receiving eribulin in daily practice not necessarily meet all the eligibility criteria of clinical trials, data for such patients are limited Methods: We identified patients with locally advanced or metastatic breast cancer, treated with eribulin monotherapy between July 2011 and December 2015 at the National Cancer Center Hospital, Tokyo, Japan Patients who would have met the following eligibility criteria from the EMBRACE trial were included in the eligible group, and the rest were included in the ineligible group: 1) Eastern Cooperative Oncology Group Performance status 0–2; 2) adequate function of principal organs; and 3) absence of active infection We compared the relative dose intensity (RDI), tumor response, progression-free survival (PFS), overall survival (OS), and adverse events between the groups Nominal and continuous values were compared using the Fisher’s exact test and Mann-Whitney U test, respectively Survival outcomes were determined using Kaplan-Meier estimation, and between-group differences were assessed using the log-rank test Results: Of the 203 patients included, 34 were classified into the ineligible group and 169 into the eligible group Initial dose reduction and treatment discontinuation due to adverse events (AEs) were more common in the ineligible group (initial dose reduction: 23.5% in the ineligible group vs 7.7% in the eligible group, p = 0.011; treatment discontinuation due to AEs: 11.8% vs 3.0%, p = 0.045) However, RDI (66% vs 71%, p = 0.130), response rate (15.6% vs 18.1%, p = 1.000), PFS (3.7 months vs 4.0 months, p = 0.913), OS (11.5 months vs 16.1 months, p = 0.743), AEs requiring hospitalization (5 9% vs 6.5%, p = 1.000), and grade 3/4 AEs were similar in both groups PFS, OS, AEs requiring hospitalization, and discontinuation due to AEs in the eligible group were comparable to those found in previous phase III trials Conclusion: The safety and efficacy of eribulin monotherapy was demonstrated in a broader patient population than that eligible for clinical trials Eribulin may be a treatment option in these patients with locally advanced or metastatic breast cancer, considering dose reduction and pre-existing dysfunctions Keywords: Breast cancer, Eribulin, Efficacy, Safety * Correspondence: tshimoi@ncc.go.jp Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, 3-1-3 Hongoh, bunkyo-ku, Tokyo 113-0033, Japan Full list of author information is available at the end of the article © The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated Iizumi et al BMC Cancer (2017) 17:819 Backgroud Breast cancer is the most common cancer and leading cause of cancer mortality in women worldwide [1] Despite recent developments in treatment, metastatic breast cancer remains incurable, and the 5-year survival rate is only 26% [2] The goals of treatment are to prolong survival and to improve or maintain quality of life Chemotherapy plays an important role, especially in patients with hormone-receptor negative or endocrine-resistant breast cancer However, few chemotherapeutic agents have been shown to prolong overall survival (OS) While anthracyclines and taxanes are commonly used as standard first-line therapy in the metastatic setting, there is no single optimal subsequent-line chemotherapy [3] Eribulin mesylate is a microtubule-inhibitor with a different mechanism from that of taxanes It is the only chemotherapeutic agent shown to increase OS after treatment failure with anthracyclines and taxanes Its efficacy and safety have been demonstrated in clinical trials, including two phase III trials, the EMBRACE and Study 301 [4, 5] In addition to trial populations, its efficacy and safety in real-world populations have been reported in retrospective studies [6–10] Also, a recently-published meta-analysis of retrospective series provides important clinical implications, by comparing the outcomes of eribulin in clinical practice and those from trials [11] However, the efficacy and safety, specifically in patients who would not have participated in clinical trials, but who still receive eribulin in daily practice, have not been reported We conducted a retrospective study to assess the efficacy and safety of eribulin in patients with locally advanced or metastatic breast cancer who would not have met the eligibility criteria of the EMBRACE trial Methods Patients We retrieved the medical records of patients with locally advanced or metastatic, pathologically confirmed breast cancer treated with eribulin monotherapy between July 2011 and December 2015 at the National Cancer Center Hospital (Tokyo, Japan) Patients who received eribulin at different hospitals before being treated at our hospital or those with insufficient data regarding trial eligibility were excluded from the analysis Definition of patient analysis groups (trial eligible and trial ineligible) We determined the eligibility of patients included in this analysis according to the following criteria based on the EMBRACE trial: 1) Eastern Cooperative Oncology Group Performance status (PS) of to 2; 2) adequate function of principal organs (adequate bone marrow, renal, and liver function as evidenced by absolute neutrophil count ≥1500/ Page of mm3, platelets ≥10 × 104/mm3, hemoglobin ≥10 g/dL, serum creatinine ≤2.0 mg/dL, total bilirubin ≤1.5 times the upper limit of normal [ULN], and aspartate transaminase [AST] and alanine transaminase [ALT] ≤ three times ULN, [AST and ALT ≤ five times ULN in patients with liver metastasis]); and 3) absence of active infection Patients satisfying all these criteria were classified into the “eligible group”; patients not satisfying any one of these criteria were classified into the “ineligible group.” We selected the criteria that may independently affect the efficacy (or dose intensity [DI]) or safety of eribulin and that were welldocumented by the medical records We considered that factors regarding prior chemotherapy (including the no of prior chemotherapy lines) not affect the efficacy or safety of eribulin by themselves; thus, we did not include them for the criteria for the classification Life expectancy, stable brain metastasis, and peripheral neuropathy were not included because they were not necessarily welldocumented at the initiation of eribulin Treatment Patients received intravenous infusions of eribulin mesylate 1.4 mg/m2 over 2–5 on days and of each 21-day cycle The dosing was adjusted according to dose modification recommended by the FDA prescribing information [12], adverse events, or the physicians’ judgment Treatment cycles were repeated until progressive disease or unacceptable toxicity, or until the patient decided to terminate treatment Assessment We assessed tumor response according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 [13] by using computed tomography (CT) scans CT scans were obtained every other cycle or sooner if needed Confirmation of response was not required Response rate (RR) and disease control rate (DCR) were defined as proportions of patients who achieved at least partial response and stable disease as best response, respectively Progression-free survival (PFS) was defined as the time from the initiation of eribulin monotherapy until either clinical or objective disease progression, or death OS was defined as the time from the initiation of eribulin monotherapy until death We also assessed relative dose intensity (RDI), DI and planned dose intensity (PDI) according to the following formula: RDI (%) = DI/PDI ×100, DI (mg/week) = Cumulative dose/treatment duration, PDI (mg/week) =1.4 × 2/3 Adverse events (AEs) were assessed using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 Iizumi et al BMC Cancer (2017) 17:819 Statistical analysis The study was designed to compare the efficacy (RR, DCR, PFS, and OS) and safety (frequency of grade or worse AEs, discontinuation due to AEs, and AEs requiring hospitalization) of eribulin between the eligible group and the ineligible group Nominal values and continuous values were compared using Fisher’s exact test and Mann-Whitney U test, respectively Only patients with target lesions were analyzed for RR and DCR Survival outcomes were obtained using Kaplan-Meier estimates, and the differences between the two groups were assessed using log-rank test Tests were considered significant if the two-sided p-value was 3 x ULN (5 x ULN in liver metastasis) (14.7) G3 Absolute neutrophil count